Novel substituted quinoline-8-carbonitrile derivatives with androgen receptor degradation activity and uses thereof

ABSTRACT

The present disclosure relates to novel compounds, pharmaceutical compositions containing such compounds, and their use in prevention and treatment of cancer and related diseases and conditions. In some embodiments, the compounds disclosed herein exhibit androgen receptor degradation activity.

This application claims priority from U.S. Provisional PatentApplication No. 62/904,017, filed Sep. 23, 2019, which is herebyincorporated by reference in its entirety.

FIELD OF THE DISCLOSURE

The present disclosure relates to novel compounds, pharmaceuticalcompositions containing such compounds, and their use in prevention andtreatment of diseases and conditions, e.g., cancer. The compoundsdisclosed herein exhibit androgen receptor degradation activity.

BACKGROUND OF THE DISCLOSURE

Androgens, through binding to the Androgen Receptor (AR), govern a widerange of physiological processes. For example, androgens are requiredfor normal prostate development and function as they are key in the ARsignaling pathway. Unfortunately, the AR signaling pathway is alsoimplicated in the development and survival of cancers, such as prostate,breast, and other cancers (see, e.g., “Androgen Receptor in ProstateCancer”, Endocrine Reviews, 2004, 25(2), 276-308; and “Androgenreceptors beyond prostate cancer: ann old marker as a new target”,Oncotarget, 2014, 6(2), 592-603).

Traditional methods to treat cancers where AR is implicated, such asprostate cancer, involves AR signaling suppression through, for example,androgen deprivation therapy. Such therapy includes chemical and/orsurgical castration. Alternatively, anti-androgen therapy may bepursued, whereby a patient is treated with an AR inhibitor, such asenzalutamide (XTANDI®). Although these treatment methods have resultedin improved prognoses for individuals with androgen receptor positivecancer, cancer progression is eventually observed and occurs through,for example, AR gene amplification and/or development of AR mutations.

Accordingly, there exists a need to treat AR positive cancer that haltsprogression of the cancer, even if the individual has experienced one ormore prior therapies. One approach to achieve this goal would be toutilize the naturally occurring cellular ubiquitin-mediated degradation.Without being bound to any theory, it is believed that AR degradationmay occur when both AR and a ubiquitin ligase are bound and brought intoclose proximity.

Cereblon (“CRBN”) E3 ubiquitin ligase is a ubiquitin ligase that formsan E3 ubiquitin ligase complex with damaged DNA binding protein 1 andCullin 4. It functions as a substrate receptor by bringing thesubstrates to close proximity for ubiquitination and subsequentdegradation by proteasomes. Recently, it has been discovered that smallmolecules drugs, e.g., thalidomide and its close analogs, lenalidomideand pomalidomide, can simultaneously interact with CRBN and some otherproteins. In doing so, CRBN may be exploited for target proteindegradation, such as IKZF1 and IKZF3. This is thought to account for theanti-myeloma effects of thalidomide and related compounds.

Thus, disclosed herein are compounds useful for the treatment ofcancers, such as prostate cancer. In some instances, the cancer is ARpositive. The compounds disclosed herein are bifunctional molecules,where one portion of the molecule is capable of interacting with CRBNand the other portion, which is linked to the CRBN-interacting portionof the molecule via a linking moiety, is capable of interacting with AR.

SUMMARY OF THE DISCLOSURE

In some embodiments, the present disclosure is directed to a compound ofFormula (1), or a pharmaceutically acceptable salt thereof:

wherein:

X₁ is CR₁ or N;

X₂ is CR₂ or N;

X₃ is CR₃ or N;

X₄ is CR₄ or N;

each of R₁, R₂, R₃, and R₄ is independently selected from hydrogen,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkyl, each of which is substitutedwith 0, 1, 2, or 3 R_(S);

each R₅ is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN, each of which issubstituted with 0, 1, 2, or 3 R_(S);

each R₆ is independently selected from hydrogen, halogen, C₁-C₃alkyl,and C₁-C₃haloalkyl, each of which is substituted with 0, 1, 2, or 3R_(S), or two R₆ groups are taken together to form an oxo;

each R₇ is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN, each of which issubstituted with 0, 1, 2, or 3 R_(S);

each R₈ is independently selected from hydrogen, hydroxyl, C₁-C₃alkyl,and C₁-C₃haloalkyl, each of which is substituted with 0, 1, 2, or 3R_(S), or two R₈ groups are taken together to form an oxo;

each R₉ is independently selected from hydrogen, C₁-C₃alkyl,—C(═O)—(C₁-C₃alkyl), —C(═O)—O—(C₁-C₃alkyl), and —C(═O)—NH—(C₁-C₃alkyl),each of which is substituted with 0, 1, 2, or 3 R_(S), or two R₉ groupsare taken together to form a 3- to 6-membered heterocycle or heteroaryl;

each R_(S) is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN;

L is a linker of 1 to 16 carbon atoms in length, wherein one or morecarbon atoms are optionally replaced by C(O), O, N(R₉), S, C₂-alkenyl,C₂-alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein theR₉, C₂-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are eachindependently substituted with 0, 1, 2, or 3 R_(S);

m is 0, 1, or 2;

n is 0, 1, 2, or 3; and

o is 0, 1, 2, or 3,

wherein each hydrogen atom is independently and optionally replaced by adeuterium atom.

In some embodiments, the compound of Formula (1) may be a compound ofFormula (1A)

In some embodiments, the

group is selected from

In some embodiments, the

group may be selected from

In some embodiments,

the group may be selected from

In some embodiments, L may be selected from:

Also disclosed herein is a method of treating cancer, in a subject inneed thereof, comprising administering to said subject a compound ofFormula (1) (e.g. Formula (1A)) or pharmaceutically acceptable saltthereof, or a pharmaceutical composition comprising a compound ofFormula (1) or a pharmaceutically acceptable salt thereof. In at leastone embodiment, the pharmaceutical composition of the present disclosuremay be for use in (or in the manufacture of medicaments for) thetreatment of cancer in the subject in need thereof.

In at least one embodiment, a therapeutically-effective amount of apharmaceutical composition of the present disclosure may be administeredto a subject diagnosed with cancer. In some embodiments, the cancer isselected from prostate cancer, head and neck cancer, skin cancer,sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer,lung cancer, gastric carcinoma, esophageal carcinoma, pancreaticadenocarcinoma, colorectal cancer, connective tissue cancer,glioblastoma multiforme, cervical cancer, uterine cancer, ovariancancer, and breast cancer.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate the disclosed embodiments and,together with the description, explain the principles of the disclosedembodiments. In the drawings:

FIG. 1 illustrates the androgen receptor (AR) degradative activity ofcompounds 3-13 and 3-29 in LNCAP cell lines 24 hours afteradministration using Western blot analysis.

DETAILED DESCRIPTION OF THE DISCLOSURE Definitions

As used herein, “cancer” refers to diseases, disorders, and conditionsthat involve abnormal cell growth with the potential to invade or spreadto other parts of the body. Exemplary cancers include, but are notlimited to, prostate cancer, head and neck cancer, skin cancer, sarcoma,renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lungcancer, gastric carcinoma, esophageal carcinoma, pancreaticadenocarcinoma, colorectal cancer, connective tissue cancer,glioblastoma multiforme, cervical cancer, uterine cancer, ovariancancer, and breast cancer.

As used herein, the term “androgen receptor positive” means thatandrogen receptor is detected by one or more analytical methods, e.g.,immunohistochemistry. For example, analysis of a biopsy of a subject'stumor may indicate the presence of androgen receptor. AR status may betested by circulating cancer cells or circulating tumor DNA in a bloodtest. In some circumstances an AR test may not be performed.

“Subject” refers to an animal, such as a mammal, that has been or willbe the object of treatment, observation, or experiment. The methodsdescribed herein may be useful for both human therapy and veterinaryapplications. In one embodiment, the subject is a human.

As used herein, “treatment” or “treating” refers to an amelioration of adisease or disorder, or at least one discernible symptom thereof. Inanother embodiment, “treatment” or “treating” refers to an ameliorationof at least one measurable physical parameter, not necessarilydiscernible by the patient. In yet another embodiment, “treatment” or“treating” refers to inhibiting the progression of a disease ordisorder, either physically, e.g., stabilization of a discerniblesymptom, physiologically, e.g., stabilization of a physical parameter,or both. In yet another embodiment, “treatment” or “treating” refers todelaying the onset of a disease or disorder.

A dash (“—”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CN isattached through the carbon atom.

By “optional” or “optionally” it is meant that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where the event or circumstance occursand instances in which is does not. It will be understood by thoseskilled in the art, with respect to any group containing one or moresubstituents, that such groups are not intended to introduce anysubstitution or substitution patterns that are sterically impractical,synthetically non-feasible and/or inherently unstable.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example, “C₁-C₆ alkyl” is intendedto encompass C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋ ₆, C₄₋₅, and C₅₋₆ alkyl.

The term “alkenyl” as used herein refers to an unsaturated, two-carbongroup having a carbon-carbon double bond, referred to herein asC₂-alkenyl.

The term “alkoxy” as used herein refers to an alkyl or cycloalkylcovalently bonded to an oxygen atom.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-8 carbonatoms, referred to herein as (C₁-C₈)alkyl. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, andoctyl. In some embodiments, “alkyl” is a straight-chain hydrocarbon. Insome embodiments, “alkyl” is a branched hydrocarbon.

The term “alkynyl” as used herein refers to an unsaturated, two-carbongroup having a carbon-carbon triple bond, referred to herein asC₂-alkynyl.

The term “aryl” as used herein refers to a mono-, bi-, or othermulti-carbocyclic, aromatic ring system with 5 to 14 ring atoms. Thearyl group can optionally be fused to one or more rings selected fromaryls, cycloalkyls, heteroaryls, and heterocyclyls. The aryl groups ofthis present disclosure can be substituted with groups selected fromalkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.Exemplary aryl groups include, but are not limited to, phenyl, tolyl,anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well asbenzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.Exemplary aryl groups also include but are not limited to a monocyclicaromatic ring system, wherein the ring comprises 6 carbon atoms,referred to herein as “C₆-aryl.”

The term “cycloalkyl” as used herein refers to a saturated orunsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of3-16 carbons, or 3-8 carbons, referred to herein as “(C₃-C₈)cycloalkyl,”derived from a cycloalkane. Exemplary cycloalkyl groups include, but arenot limited to, cyclohexanes, cyclohexenes, cyclopentanes, andcyclopentenes. Cycloalkyl groups may be substituted with alkoxy,aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Cycloalkyl groups can be fused to other cycloalkyl (saturated orpartially unsaturated), aryl, or heterocyclyl groups, to form a bicycle,tetracycle, etc. The term “cycloalkyl” also includes bridged andspiro-fused cyclic structures which may or may not contain heteroatoms.

The terms “halo” or “halogen” as used herein refer to —F, —Cl, —Br,and/or —I.

The term “haloalkyl group” as used herein refers to an alkyl groupsubstituted with one or more halogen atoms.

The term “heteroaryl” as used herein refers to a mono-, bi-, ormulti-cyclic, aromatic ring system containing one or more heteroatoms,for example 1-4 heteroatoms, such as nitrogen, oxygen, and sulfur.Heteroaryls can be substituted with one or more substituents includingalkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Heteroaryls can also be fused to non-aromatic rings. Illustrativeexamples of heteroaryl groups include, but are not limited to,pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl,pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl,pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl,phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include,but are not limited to, a monocyclic aromatic ring, wherein the ringcomprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as“(C₂-C₅)heteroaryl.” In some embodiments, a heteraryl contains 5 to 10ring atoms, 1 to 4 of which are heteroatoms selected from N, O, and S.In some embodiments, a heteroaryl contains 5 to 8 ring atoms, 1 to 4 ofwhich are heteroatoms selected from N, O, and S.

The terms “heterocycle,” “heterocyclyl,” or “heterocyclic” as usedherein each refer to a saturated or unsaturated 3- to 18-membered ringcontaining one, two, three, or four heteroatoms independently selectedfrom nitrogen, oxygen, phosphorus, and sulfur. Heterocycles can bearomatic (heteroaryls) or non-aromatic. Heterocycles can be substitutedwith one or more substituents including alkoxy, aryloxy, alkyl, alkenyl,alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl,sulfonyl, sulfonic acid, sulfonamide and thioketone. Heterocycles alsoinclude bicyclic, tricyclic, and tetracyclic groups in which any of theabove heterocyclic rings is fused to one or two rings independentlyselected from aryls, cycloalkyls, and heterocycles. Exemplaryheterocycles include acridinyl, benzimidazolyl, benzofuryl,benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl,dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl,dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl,imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl,isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl,oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl,pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl,pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl,quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl,tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl,thienyl, thiomorpholinyl, thiopyranyl, and triazolyl. In someembodiments, a heterocycle contains 5 to 10 ring atoms, 1 to 4 of whichare heteroatoms selected from N, O, and S. In some embodiments, aheterocycle contains 5 to 8 ring atoms, 1 to 4 of which are heteroatomsselected from N, O, and S.

The terms “hydroxy” and “hydroxyl” as used herein refer to —OH.

The term “oxo” as used herein refers to a double bond to an oxygen atom(i.e., ═O). For example, when two geminal groups on a carbon atom are“taken together to form an oxo”, then a carbonyl (i.e., C═O) is formed.

The term “pharmaceutically acceptable carrier” as used herein refers toany and all solvents, dispersion media, coatings, isotonic andabsorption delaying agents, and the like, that are compatible withpharmaceutical administration. The use of such media and agents forpharmaceutically active substances is well known in the art. Thecompositions may also contain other active compounds providingsupplemental, additional, or enhanced therapeutic functions.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt form of a compound of this disclosure wherein the salt is nontoxic.Pharmaceutically acceptable salts of the compounds of this disclosureinclude those derived from suitable inorganic and organic acids andbases. A “free base” form of a compound, for example, does not containan ionically bonded salt.

The phrase “and pharmaceutically acceptable salts and deuteratedderivatives thereof” is used interchangeably with “and pharmaceuticallyacceptable salts thereof and deuterated derivatives of any of theforgoing” in reference to one or more compounds or formulae of thedisclosure. These phrases are intended to encompass pharmaceuticallyacceptable salts of any one of the referenced compounds, deuteratedderivatives of any one of the referenced compounds, and pharmaceuticallyacceptable salts of those deuterated derivatives.

One of ordinary skill in the art would recognize that, when an amount of“a compound or a pharmaceutically acceptable salt thereof” is disclosed,the amount of the pharmaceutically acceptable salt form of the compoundis the amount equivalent to the concentration of the free base of thecompound. It is noted that the disclosed amounts of the compounds ortheir pharmaceutically acceptable salts thereof herein are based upontheir free base form.

Suitable pharmaceutically acceptable salts are, for example, thosedisclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66,1-19. For example, Table 1 of that article provides the followingpharmaceutically acceptable salts:

TABLE 1 Acetate Iodide Benzathine Benzenesulfonate IsethionateChloroprocaine Benzoate Lactate Choline Bicarbonate LactobionateDiethanolamine Bitartrate Malate Ethylenediamine Bromide MaleateMeglumine Calcium edetate Mandelate Procaine Camsylate Mesylate AluminumCarbonate Methylbromide Calcium Chloride Methylnitrate Lithium CitrateMethylsulfate Magnesium Dihydrochloride Mucate Potassium EdetateNapsylate Sodium Edisylate Nitrate Zinc Estolate Pamoate (Embonate)Esylate Pantothenate Fumarate Phosphate/diphosphate GluceptatePolygalacturonate Gluconate Salicylate Glutamate StearateGlycollylarsanilate Subacetate Hexylresorcinate Succinate HydrabamineSulfate Hydrobromide Tannate Hydrochloride Tartrate HydroxynaphthoateTeociate Triethiodide

Non-limiting examples of pharmaceutically acceptable acid addition saltsinclude: salts formed with inorganic acids, such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid;salts formed with organic acids, such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acid;and salts formed by using other methods used in the art, such as ionexchange. Non-limiting examples of pharmaceutically acceptable saltsinclude adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts.Pharmaceutically acceptable salts derived from appropriate bases includealkali metal, alkaline earth metal, ammonium, and N⁺(C₁₋₄alkyl)₄ salts.This disclosure also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. Suitablenon-limiting examples of alkali and alkaline earth metal salts includesodium, lithium, potassium, calcium, and magnesium. Further non-limitingexamples of pharmaceutically acceptable salts include ammonium,quaternary ammonium, and amine cations formed using counterions such ashalide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and aryl sulfonate. Other suitable, non-limiting examples ofpharmaceutically acceptable salts include besylate and glucosaminesalts.

As used herein, nomenclature for compounds including organic compounds,can be given using common names, IUPAC, IUBMB, or CAS recommendationsfor nomenclature. One of skill in the art can readily ascertain thestructure of a compound if given a name, either by systemic reduction ofcompound structure using naming conventions, or by commerciallyavailable software, such as CHEMDRAW™ (Cambridgesoft Corporation,U.S.A.).

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present disclosure encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly. In some embodiments, an enantiomer orstereoisomer may be provided substantially free of the correspondingenantiomer.

In some embodiments, the compound is a racemic mixture of (S)- and(R)-isomers. In other embodiments, provided herein is a mixture ofcompounds wherein individual compounds of the mixture existpredominately in an (S)- or (R)-isomeric configuration. For example, thecompound mixture has an (S)-enantiomeric excess of greater than about55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about99.5%, or more. In other embodiments, the compound mixture has an(S)-enantiomeric excess of greater than about 55% to about 99.5%,greater than about 60% to about 99.5%, greater than about 65% to about99.5%, greater than about 70% to about 99.5%, greater than about 75% toabout 99.5%, greater than about 80% to about 99.5%, greater than about85% to about 99.5%, greater than about 90% to about 99.5%, greater thanabout 95% to about 99.5%, greater than about 96% to about 99.5%, greaterthan about 97% to about 99.5%, greater than about 98% to greater thanabout 99.5%, greater than about 99% to about 99.5%, or more. In otherembodiments, the compound mixture has an (R)-enantiomeric purity ofgreater than about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about98%, about 99%, about 99.5% or more. In some other embodiments, thecompound mixture has an (R)-enantiomeric excess of greater than about55% to about 99.5%, greater than about 60% to about 99.5%, greater thanabout 65% to about 99.5%, greater than about 70% to about 99.5%, greaterthan about 75% to about 99.5%, greater than about 80% to about 99.5%,greater than about 85% to about 99.5%, greater than about 90% to about99.5%, greater than about 95% to about 99.5%, greater than about 96% toabout 99.5%, greater than about 97% to about 99.5%, greater than about98% to greater than about 99.5%, greater than about 99% to about 99.5%or more.

Individual stereoisomers of compounds of the present disclosure can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby: (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary; (2) salt formation employing an opticallyactive resolving agent; or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers bywell-known methods, such as chiral-phase gas chromatography,chiral-phase high performance liquid chromatography, crystallizing thecompound as a chiral salt complex, or crystallizing the compound in achiral solvent. Stereoisomers can also be obtained fromstereomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

Geometric isomers can also exist in the compounds of the presentdisclosure. The present disclosure encompasses the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond or arrangement ofsubstituents around a carbocyclic ring. Substituents around acarbon-carbon double bond are designated as being in the “Z” or “E”configuration wherein the terms “Z” and “E” are used in accordance withIUPAC standards. Unless otherwise specified, structures depicting doublebonds encompass both the E and Z isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangements of substituentsaround a carbocyclic ring are designated as “cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ringand the term “trans” represents substituents on opposite sides of theplane of the ring. Mixtures of compounds wherein the substituents aredisposed on both the same and opposite sides of plane of the ring aredesignated “cis/trans.”

The compounds disclosed herein may exist as tautomers and bothtautomeric forms are intended to be encompassed by the scope of thepresent disclosure, even if only one tautomeric structure is depicted.

Additionally, unless otherwise stated, structures described herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of hydrogen by deuterium(²H) or tritium (³H), or the replacement of a carbon by a ¹³C- or¹⁴C-carbon atom are within the scope of this disclosure. Such compoundsmay be useful as, for example, analytical tools, probes in biologicalassays, or therapeutic agents.

Compounds

In some embodiments, provided herein are compounds of Formula (1), or atautomer, stereoisomer, or pharmaceutically acceptable salt thereof, anddeuterated derivatives of any of the foregoing:

wherein:

X₁ is CR₁ or N;

X₂ is CR₂ or N;

X₃ is CR₃ or N;

X₄ is CR₄ or N;

each of R₁, R₂, R₃, and R₄ is independently selected from hydrogen,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkyl, each of which is substitutedwith 0, 1, 2, or 3 R_(S);

each R₅ is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN, each of which issubstituted with 0, 1, 2, or 3 R_(S);

each R₆ is independently selected from hydrogen, halogen, C₁-C₃alkyl,and C₁-C₃haloalkyl, each of which is substituted with 0, 1, 2, or 3R_(S), or two R₆ groups are taken together to form an oxo;

each R₇ is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN, each of which issubstituted with 0, 1, 2, or 3 R_(S);

each R₈ is independently selected from hydrogen, hydroxyl, C₁-C₃alkyl,and C₁-C₃haloalkyl, each of which is substituted with 0, 1, 2, or 3R_(S), or two R₈ groups are taken together to form an oxo;

each R₉ is independently selected from hydrogen, C₁-C₃alkyl,—C(═O)—(C₁-C₃alkyl), —C(═O)—O—(C₁-C₃alkyl), and —C(═O)—NH—(C₁-C₃alkyl),each of which is substituted with 0, 1, 2, or 3 R_(S), or two R₉ groupsare taken together to form a 3- to 6-membered heterocycle or heteroaryl;

each R_(S) is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN;

L is a linker of 1 to 16 carbon atoms in length, wherein one or morecarbon atoms are optionally replaced by C(O), O, N(R₉), S, C₂-alkenyl,C₂-alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein theR₉, C₂-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are eachindependently substituted with 0, 1, 2, or 3 R_(S);

m is 0, 1, or 2;

n is 0, 1, 2, or 3; and

o is 0, 1, 2, or 3,

wherein each hydrogen atom is independently and optionally replaced by adeuterium atom.

In some embodiments, the compound of Formula (1) may be a compound ofFormula (1A)

In some embodiments, X₁ is N. In some embodiments, X₂ is N. In someembodiments, X₁ and X₂ are each N. In some embodiments, X₂ is CR₂, X₃ isCR₃, and X₄ is CR₄. In some embodiments, R₂, R₃, and R₄ are eachindependently selected from H and F. In some embodiments, X₂ is CR₂, X₃is CR₃, X₄ is CR₄, and R₂, R₃, and R₄ are each independently selectedfrom H and F. In some embodiments, X₁ is CR₁, X₂ is CR₂, X₃ is CR₃, andX₄ is CR₄. In some embodiments, R₁, R₂, R₃, and R₄ are eachindependently selected from H and F. In some embodiments, X₁ is CR₁, X₂is CR₂, X₃ is CR₃, and X₄ is CR₄, and R₁, R₂, R₃, and R₄ are eachindependently selected from H and F.

In some embodiments, R₁ is F. In some embodiments, R₂ is F. In someembodiments, R₃ is F. In some embodiments, R₄ is F. In some embodiments,R₁ and R₃ are each F. In some embodiments, R₃ and R₄ are each F. In someembodiments, R₂, R₃, and R₄ are each H. In some embodiments, R₁, R₃, andR₄ are each H. In some embodiments, R₁, R₂, and R₄ are each H. In someembodiments, R₁, R₂, and R₃ are each H. In some embodiments, R₂ and R₄are each H. In some embodiments, R₁ and R₂ are each H.

In some embodiments, the

group is selected from

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, each R₅ is independently selected from halogen,C₁-C₃alkoxy, and C₁-C₃haloalkyl. In some embodiments, each R₅ isindependently selected from —Cl, —OCH₃, and —CF₃.

In some embodiments, m is 0 or 1. In some embodiments, m is 0. In someembodiments, m is 1.

In some embodiments, o is 0 or 1. In some embodiments, o is 0. In someembodiments, o is 1.

In some embodiments, m and o are each 0.

In some embodiments, each R₆ is independently selected from H andC₁-C₃alkyl. In some embodiments, each R₆ is independently selected fromH and —CH₃. In some embodiments, one R₆ is H and the other R₆ is —CH₃.In some embodiments, each R₆ is identical. In some embodiments, each R₆is different.

In some embodiments, each

group is selected from

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

is selected from

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, each R₇ is independently selected from halogen,hydroxyl, C₁-C₃alkyl, and C₁-C₃haloalkyl. In some embodiments, each R₇is independently selected from halogen, hydroxyl, —CH₃, and —CF₃. Insome embodiments, each R₇ is independently selected from F, hydroxyl,—CH₃, and —CF₃. In some embodiments, each R₇ is independently F.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, each R₈ is hydrogen or two R₈ groups are takentogether to form an oxo. In some embodiments, each R₈ is hydrogen. Insome embodiments, two R₈ groups are taken together to form an oxo.

In some embodiments, the

group is

In some embodiments, the

group is selected from

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments,

the group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, each R₉ is independently selected from hydrogen,C₁-C₃alkyl, and —C(═O)—C₁-C₃alkyl. In some embodiments, each R₉ isindependently selected from hydrogen and C₁-C₃alkyl. In someembodiments, each R₉ is independently selected from hydrogen, —CH₃,—CH₂CH₃, and —CH(CH₃)₂.

In some embodiments, L is a linker of 1 to 12 carbon atoms in length,wherein one or more carbon atoms are optionally replaced by C(═O), O,N(R₉), S, C₂-alkenyl, C₂-alkynyl, cycloalkyl, aryl, heterocycle, orheteroaryl, wherein the R₉, C₂-alkenyl, cycloalkyl, aryl, heterocycle,and heteroaryl are each independently substituted with 0, 1, 2, or 3R_(S). In some embodiments, L is a linker of 1 to 10 carbon atoms inlength, wherein one or more carbon atoms are optionally replaced byC(═O), O, N(R₉), S, C₂-alkenyl, C₂-alkynyl, cycloalkyl, aryl,heterocycle, or heteroaryl, wherein the R₉, C₂-alkenyl, cycloalkyl,aryl, heterocycle, and heteroaryl are each independently substitutedwith 0, 1, 2, or 3 R_(S). In some embodiments, L is a linker of 1 to 8carbon atoms in length, wherein one or more carbon atoms are optionallyreplaced by C(═O), O, N(R₉), S, C₂-alkenyl, C₂-alkynyl, cycloalkyl,aryl, heterocycle, or heteroaryl, wherein the R₉, C₂-alkenyl,cycloalkyl, aryl, heterocycle, and heteroaryl are each independentlysubstituted with 0, 1, 2, or 3 R_(S). In some embodiments, L is a linkerof 1 to 6 carbon atoms in length, wherein one or more carbon atoms areoptionally replaced by C(═O), O, N(R₉), S, C₂-alkenyl, C₂-alkynyl,cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the R₉,C₂-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are eachindependently substituted with 0, 1, 2, or 3 R_(S).

In some embodiments, one or more carbon atoms of linker L are optionallyreplaced by C(═O), O, N(R₉), S, cycloalkyl, aryl, heterocycle, orheteroaryl. In some embodiments, one or more carbon atoms of linker Lare optionally replaced by 0, N(R₉), cycloalkyl, or heterocycle, whereinthe R₉, cycloalkyl, and heterocycle are each independently substitutedwith 0, 1, 2, or 3 R_(S). In some embodiments, at least one carbon atomof linker L is replaced by a heterocycle, which is substituted with 0,1, 2, or 3 R_(S). In some embodiments, at least two carbon atoms oflinker L are replaced by a heterocycle, each of which is substitutedwith 0, 1, 2, or 3 R_(S).

In some embodiments, the heterocycle in L is selected from piperidineand piperazine, each of which is substituted with 0, 1, 2, or 3 R_(S).In some embodiments, the heterocycle in L is selected from

In some embodiments, L is selected from:

In some embodiments, provided herein is a pharmaceutically acceptablesalt of a compound of Formula (1). In some embodiments, provided hereinis a deuterated derivative of a pharmaceutically acceptable salt of acompound of Formula (1). In some embodiments, provided herein is acompound of Formula (1). In some embodiments, provided herein is acompound of Formula (1A).

In some embodiments, provided herein is a compound chosen from thecompounds listed in Table 2 or a tautomer, stereoisomer, orpharmaceutically acceptable salt thereof, or a deuterated derivative ofany of the foregoing.

TABLE 2 Exemplary Compounds of the Present Disclosure Reference #Structure & Name Number  1

3-1   2

3-2   3

3-3   4

3-4   5

3-5   6

3-6   7

3-7   8

3-8   9

3-9  10

3-10 11

3-11 12

3-12 13

3-13 14

3-14 15

3-15 16

3-16 17

3-17 18

3-18 19

3-19 20

3-20 21

3-21 22

3-22 23

3-23 24

3-24 25

3-25 26

3-26 27

3-27 28

3-28 29

3-29 30

3-30 31

3-31 32

3-32 33

3-33 34

3-34 35

3-35 36

3-36 37

3-37 38

3-38 39

3-39 40

3-40 41

3-41 42

3-42 43

3-43 44

3-44 45

3-45 46

3-46 47

3-47 48

3-48 49

3-49 50

3-50 51

3-51 52

3-52 53

3-53 54

3-54 55

3-55

Pharmaceutical Compositions

Pharmaceutical compositions of the present disclosure comprise at leastone compound of Formula (1) (e.g. Formula (1A)), or a tautomer,stereoisomer, or pharmaceutically acceptable salt thereof, or adeuterated derivative of any of the foregoing formulated together with apharmaceutically acceptable carrier. These formulations include thosesuitable for oral, rectal, topical, buccal and parenteral (e.g.,subcutaneous, intramuscular, intradermal, or intravenous)administration. The most suitable form of administration in any givencase will depend on the degree and severity of the condition beingtreated and on the nature of the particular compound being used.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of a compound of the presentdisclosure as powder or granules; as a solution or a suspension in anaqueous or non-aqueous liquid; or as an oil-in-water or water-in-oilemulsion. As indicated, such formulations may be prepared by anysuitable method of pharmacy which includes the step of bringing intoassociation at least one compound of the present disclosure as theactive compound and a carrier or excipient (which may constitute one ormore accessory ingredients). The carrier must be acceptable in the senseof being compatible with the other ingredients of the formulation andmust not be deleterious to the recipient. The carrier may be a solid ora liquid, or both, and may be formulated with at least one compounddescribed herein as the active compound in a unit-dose formulation, forexample, a tablet, which may contain from about 0.05% to about 95% byweight of the at least one active compound. Other pharmacologicallyactive substances may also be present including other compounds. Theformulations of the present disclosure may be prepared by any of thewell-known techniques of pharmacy consisting essentially of admixing thecomponents.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmacologicallyadministrable compositions can, for example, be prepared by, forexample, dissolving or dispersing, at least one active compound of thepresent disclosure as described herein and optional pharmaceuticaladjuvants in an excipient, such as, for example, water, saline, aqueousdextrose, glycerol, ethanol, and the like, to thereby form a solution orsuspension. In general, suitable formulations may be prepared byuniformly and intimately admixing the at least one active compound ofthe present disclosure with a liquid or finely divided solid carrier, orboth, and then, if necessary, shaping the product. For example, a tabletmay be prepared by compressing or molding a powder or granules of atleast one compound of the present disclosure, which may be optionallycombined with one or more accessory ingredients. Compressed tablets maybe prepared by compressing, in a suitable machine, at least one compoundof the present disclosure in a free-flowing form, such as a powder orgranules, which may be optionally mixed with a binder, lubricant, inertdiluent and/or surface active/dispersing agent(s). Molded tablets may bemade by molding, in a suitable machine, where the powdered form of atleast one compound of the present disclosure is moistened with an inertliquid diluent.

Formulations suitable for buccal (sub-lingual) administration includelozenges comprising at least one compound of the present disclosure in aflavored base, usually sucrose and acacia or tragacanth, and pastillescomprising the at least one compound in an inert base such as gelatinand glycerin or sucrose and acacia.

Formulations of the present disclosure suitable for parenteraladministration comprise sterile aqueous preparations of at least onecompound of Formula (1) (e.g. Formula (1A), or a tautomer, stereoisomer,or pharmaceutically acceptable salt thereof, or a deuterated derivativeof any of the foregoing, which are approximately isotonic with the bloodof the intended recipient. These preparations are administeredintravenously, although administration may also be affected by means ofsubcutaneous, intramuscular, or intradermal injection. Such preparationsmay conveniently be prepared by admixing at least one compound describedherein with water and rendering the resulting solution sterile andisotonic with the blood. Injectable compositions according to thepresent disclosure may contain from about 0.1 to about 5% w/w of theactive compound.

Formulations suitable for rectal administration are presented asunit-dose suppositories. These may be prepared by admixing at least onecompound as described herein with one or more conventional solidcarriers, for example, cocoa butter, and then shaping the resultingmixture.

Formulations suitable for topical application to the skin may take theform of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.Carriers and excipients which may be used include Vaseline, lanoline,polyethylene glycols, alcohols, and combinations of two or more thereof.The active compound (i.e., at least one compound of Formula (1) (e.g.Formula (1A), or a tautomer, stereoisomer, or pharmaceuticallyacceptable salt thereof, or a deuterated derivative of any of theforegoing) is generally present at a concentration of from about 0.1% toabout 15% w/w of the composition, for example, from about 0.5 to about2%.

The amount of active compound administered may be dependent on thesubject being treated, the subject's weight, the manner ofadministration and the judgment of the prescribing physician. Forexample, a dosing schedule may involve the daily or semi-dailyadministration of the encapsulated compound at a perceived dosage ofabout 1 μg to about 1000 mg. In another embodiment, intermittentadministration, such as on a monthly or yearly basis, of a dose of theencapsulated compound may be employed. Encapsulation facilitates accessto the site of action and allows the administration of the activeingredients simultaneously, in theory producing a synergistic effect. Inaccordance with standard dosing regimens, physicians will readilydetermine optimum dosages and will be able to readily modifyadministration to achieve such dosages.

A therapeutically effective amount of a compound or compositiondisclosed herein can be measured by the therapeutic effectiveness of thecompound. The dosages, however, may be varied depending upon therequirements of the patient, the severity of the condition beingtreated, and the compound being used. In one embodiment, thetherapeutically effective amount of a disclosed compound is sufficientto establish a maximal plasma concentration. Preliminary doses as, forexample, determined according to animal tests, and the scaling ofdosages for human administration is performed according to art-acceptedpractices.

Toxicity and therapeutic efficacy can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.Compositions that exhibit large therapeutic indices are preferable.

Data obtained from the cell culture assays or animal studies can be usedin formulating a range of dosage for use in humans. Therapeuticallyeffective dosages achieved in one animal model may be converted for usein another animal, including humans, using conversion factors known inthe art (see, e.g., Freireich et al., Cancer Chemother. Reports50(4):219-244 (1966) and the following table (Table 3) for EquivalentSurface Area Dosage Factors).

TABLE 3 Equivalent Surface Area Dosage Factors. To: Mouse Rat Monkey DogHuman From: (20 g) (150 g) (3.5 kg) (8 kg) (60 kg) Mouse 1 1/2 1/4 1/61/12 Rat 2 1 1/2 1/4 1/7 Monkey 4 2 1 3/5 1/3 Dog 6 4 3/5 1 1/2 Human 127 3 2 1

The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized.Generally, a therapeutically effective amount may vary with thesubject's age, condition, and gender, as well as the severity of themedical condition in the subject. The dosage may be determined by aphysician and adjusted, as necessary, to suit observed effects of thetreatment.

Methods of Treatment

In some embodiments, a compound of Formula (1) (e.g. Formula (1A)), or atautomer, stereoisomer, or pharmaceutically acceptable salt thereof, ora deuterated derivative of any of the foregoing, is administered totreat cancer in a subject in need thereof. In some embodiments, thecancer is chosen from prostate cancer, head and neck cancer, skincancer, sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladdercancer, lung cancer, gastric carcinoma, esophageal carcinoma, pancreaticadenocarcinoma, colorectal cancer, connective tissue cancer,glioblastoma multiforme, cervical cancer, uterine cancer, ovariancancer, and breast cancer. In some embodiments, the cancer is prostatecancer. In some embodiments, the cancer is head and neck cancer. In someembodiments, the cancer is skin cancer. In some embodiments, the canceris sarcoma. In some embodiments, the cancer is renal cell carcinoma. Insome embodiments, the cancer is adrenocortical carcinoma. In someembodiments, the cancer is bladder cancer. In some embodiments, thecancer is lung cancer. In some embodiments, the cancer is gastriccarcinoma. In some embodiments, the cancer is esophageal carcinoma. Insome embodiments, the cancer is pancreatic adenocarcinoma. In someembodiments, the cancer is colorectal cancer. In some embodiments, thecancer is connective tissue cancer. In some embodiments, the cancer isglioblastoma multiforme. In some embodiments, the cancer is cervicalcancer. In some embodiments, the cancer is uterine cancer. In someembodiments, the cancer is ovarian cancer. In some embodiments, thecancer is breast cancer.

In some embodiments, the cancer is androgen receptor positive.

In some embodiments, a compound of Formula (1) (e.g. Formula (1A), or atautomer, stereoisomer, or pharmaceutically acceptable salt thereof, ora deuterated derivative of any of the foregoing, is administered as apharmaceutical composition.

In some embodiments, the subject has been previously treated with ananti-cancer agent. In some embodiments, the anti-cancer agent isenzalutamide, apalutamide, bicalutamide, darolutamide, flutamide,abiratarone, or a combination of any of the foregoing. In someembodiments, the anti-cancer agent is enzalutamide.

In some embodiments, provided herein is a use of a compound of Formula(1), or a tautomer, stereoisomer, or pharmaceutically acceptable saltthereof, or a deuterated derivative of any of the foregoing, fortreating cancer. In some embodiments, the cancer is selected fromprostate cancer, head and neck cancer, skin cancer, sarcoma, renal cellcarcinoma, adrenocortical carcinoma, bladder cancer, lung cancer,gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma,colorectal cancer, connective tissue cancer, glioblastoma multiforme,cervical cancer, uterine cancer, ovarian cancer, and breast cancer. Insome embodiments, the cancer is prostate cancer. In some embodiments,the cancer is head and neck cancer. In some embodiments, the cancer isskin cancer. In some embodiments, the cancer is sarcoma. In someembodiments, the cancer is renal cell carcinoma. In some embodiments,the cancer is adrenocortical carcinoma. In some embodiments, the canceris bladder cancer. In some embodiments, the cancer is lung cancer. Insome embodiments, the cancer is gastric carcinoma. In some embodiments,the cancer is esophageal carcinoma. In some embodiments, the cancer ispancreatic adenocarcinoma. In some embodiments, the cancer is colorectalcancer. In some embodiments, the cancer is connective tissue cancer. Insome embodiments, the cancer is glioblastoma multiforme. In someembodiments, the cancer is cervical cancer. In some embodiments, thecancer is uterine cancer. In some embodiments, the cancer is ovariancancer. In some embodiments, the cancer is breast cancer. In someembodiments, the cancer is androgen receptor positive.

In some embodiments, provided herein is a use of a compound of Formula(1), or a tautomer, stereoisomer, or pharmaceutically acceptable saltthereof, or a deuterated derivative of any of the foregoing, in thepreparation of a medicament. In some embodiments, the medicament is forthe treatment of cancer. In some embodiments, the cancer is selectedfrom prostate cancer, head and neck cancer, skin cancer, sarcoma, renalcell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer,gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma,colorectal cancer, connective tissue cancer, glioblastoma multiforme,cervical cancer, uterine cancer, ovarian cancer, and breast cancer. Insome embodiments, the cancer is prostate cancer. In some embodiments,the cancer is head and neck cancer. In some embodiments, the cancer isskin cancer. In some embodiments, the cancer is sarcoma. In someembodiments, the cancer is renal cell carcinoma. In some embodiments,the cancer is adrenocortical carcinoma. In some embodiments, the canceris bladder cancer. In some embodiments, the cancer is lung cancer. Insome embodiments, the cancer is gastric carcinoma. In some embodiments,the cancer is esophageal carcinoma. In some embodiments, the cancer ispancreatic adenocarcinoma. In some embodiments, the cancer is colorectalcancer. In some embodiments, the cancer is connective tissue cancer. Insome embodiments, the cancer is glioblastoma multiforme. In someembodiments, the cancer is cervical cancer. In some embodiments, thecancer is uterine cancer. In some embodiments, the cancer is ovariancancer. In some embodiments, the cancer is breast cancer. In someembodiments, the cancer is androgen receptor positive.

In some embodiments, provided herein is a method of inhibiting cellgrowth comprising contacting a cell with a compound of Formula (1), or atautomer, stereoisomer, or pharmaceutically acceptable salt thereof, ora deuterated derivative of any of the foregoing. In some embodiments,the cell is a cancer cell. In some embodiments, the cancer cell is aprostate cancer cell. In some embodiments, the cell is androgen receptorpositive.

In one embodiment, a compound of Formula (1) (e.g. Formula (1A)), or atautomer, stereoisomer, pharmaceutically acceptable salt or hydratethereof, may be administered in combination with another therapeuticagent. The other therapeutic agent can provide additive or synergisticvalue relative to the administration of a compound of the presentdisclosure alone. The therapeutic agent can be selected from, forexample, hormones and hormonal analogues; signal transduction pathwayinhibitors; topoisomerase I inhibitors; topoisomerase II inhibitors;antimetabolite neoplastic agents; antibiotic neoplastic agents;alkylating agents; anti-microtubule agents; platinum coordinationcomplexes; aromatase inhibitors; and anti-mitotic agents.

In some embodiments, the therapeutic agent may be a hormone or hormonalanalogue. In some embodiments, the therapeutic agent may be a signaltransduction pathway inhibitor. In some embodiments, the therapeuticagent may be a topoisomerase I inhibitor. In some embodiments, thetherapeutic agent may be a topoisomerase II inhibitor. In someembodiments, the therapeutic agent may be an antimetabolite neoplasticagent. In some embodiments, the therapeutic agent may be an antibioticneoplastic agent. In some embodiments, the therapeutic agent may be analkylating agent. In some embodiments, the therapeutic agent may be ananti-microtubule agent. In some embodiments, the therapeutic agent maybe a platinum coordination complex. In some embodiments, the therapeuticagent may be an aromatase inhibitor. In some embodiments, thetherapeutic agent may be an anti-mitotic agent.

In some embodiments, the aromatase inhibitor may be selected fromanastrazole, letrozole, vorozole, fadrozole, exemestane, and formestane.In some embodiments, the aromatase inhibitor is anastrazole. In someembodiments, the aromatase inhibitor may be letrozole. In someembodiments, the aromatase inhibitor may be vorozole. In someembodiments, the aromatase inhibitor may be fadrozole. In someembodiments, the aromatase inhibitor may be exemestane. In someembodiments, the aromatase inhibitor may be formestane.

In some embodiments, the anti-mitotic agent may be selected frompaclitaxel, docetaxel, and Abraxane. In some embodiments, theanti-mitotic agent may be paclitaxel. In some embodiments, theanti-mitotic agent may be docetaxel. In some embodiments, theanti-mitotic agent may be Abraxane.

In some embodiments, a compound of Formula (1) (e.g. Formula (1A)), or atautomer, stereoisomer, or pharmaceutically acceptable salt thereof, ora deuterated derivative of any of the foregoing, may be administered incombination with a hormone or hormonal analog. In some embodiments, acompound of Formula (1), or a tautomer, stereoisomer, orpharmaceutically acceptable salt thereof, or a deuterated derivative ofany of the foregoing, may be administered in combination with a signaltransduction pathway inhibitor. In some embodiments, a compound ofFormula (1), or a tautomer, stereoisomer, or pharmaceutically acceptablesalt thereof, or a deuterated derivative of any of the foregoing, may beadministered in combination with an antimetabolite neoplastic agent. Insome embodiments, a compound of Formula (1), or a tautomer,stereoisomer, or pharmaceutically acceptable salt thereof, or adeuterated derivative of any of the foregoing, may be administered incombination with a topoisomerase I inhibitor. In some embodiments, acompound of Formula (1), or a tautomer, stereoisomer, orpharmaceutically acceptable salt thereof, or a deuterated derivative ofany of the foregoing, may be administered in combination with atopoisomerase II inhibitor. In some embodiments, a compound of Formula(1), or a tautomer, stereoisomer, or pharmaceutically acceptable saltthereof, or a deuterated derivative of any of the foregoing, may beadministered in combination with an aromatase inhibitor.

Examples

The examples and preparations provided below further illustrate andexemplify the compounds as disclosed herein and methods of preparingsuch compounds. It is to be understood that the scope of the presentdisclosure is not limited in any way by the scope of the followingexamples and preparations.

The chemical entities described herein can be synthesized according toone or more illustrative schemes herein and/or techniques well known inthe art. Unless specified to the contrary, the reactions describedherein take place at atmospheric pressure, generally within atemperature range from about −10° C. to about 200° C. Further, except asotherwise specified, reaction times and conditions are intended to beapproximate, e.g., taking place at about atmospheric pressure within atemperature range of about −10° C. to about 200° C. over a period thatcan be, for example, about 1 to about 24 hours; reactions left to runovernight in some embodiments can average a period of about 16 hours.

Isolation and purification of the chemical entities and intermediatesdescribed herein can be affected, if desired, by any suitable separationor purification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography orthick-layer chromatography, or a combination of these procedures. See,e.g., Carey et al. Advanced Organic Chemistry, 3^(rd) Ed., 1990 NewYork: Plenum Press; Mundy et al., Name Reaction and Reagents in OrganicSynthesis, 2^(nd) Ed., 2005 Hoboken, N.J.: J. Wiley & Sons. Specificillustrations of suitable separation and isolation procedures are givenby reference to the examples hereinbelow. However, other equivalentseparation or isolation procedures can also be used.

In all of the methods, it is well understood that protecting groups forsensitive or reactive groups may be employed where necessary, inaccordance with general principles of chemistry. Protecting groups aremanipulated according to standard methods of organic synthesis (T. W.Greene and P. G. M. Wuts (1999) Protective Groups in Organic Synthesis,3^(rd) Ed., John Wiley & Sons). These groups may be removed at aconvenient stage of the compound synthesis using methods that arereadily apparent to those skilled in the art.

When desired, the (R)- and (S)-isomers of the nonlimiting exemplarycompounds, if present, can be resolved by methods known to those skilledin the art, for example, by formation of diastereoisomeric salts orcomplexes which can be separated, e.g., by crystallization; viaformation of diastereoisomeric derivatives which can be separated, e.g.,by crystallization, gas-liquid or liquid chromatography; selectivereaction of one enantiomer with an enantiomer-specific reagent, e.g.,enzymatic oxidation or reduction, followed by separation of the modifiedand unmodified enantiomers; or gas-liquid or liquid chromatography in achiral environment, e.g., on a chiral support, such as silica with abound chiral ligand or in the presence of a chiral solvent.Alternatively, a specific enantiomer can be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting one enantiomer to the other by asymmetrictransformation.

The compounds described herein can be optionally contacted with apharmaceutically acceptable acid to form the corresponding acid additionsalts. Also, the compounds described herein can be optionally contactedwith a pharmaceutically acceptable base to form the corresponding basicaddition salts.

In some embodiments, disclosed compounds can generally be synthesized byan appropriate combination of generally well-known synthetic methods.Techniques useful in synthesizing these chemical entities are bothreadily apparent and accessible to those of skill in the relevant art,based on the instant disclosure. Many of the optionally substitutedstarting compounds and other reactants are commercially available, e.g.,from Millipore Sigma or can be readily prepared by those skilled in theart using commonly employed synthetic methodology.

The discussion below is offered to illustrate certain of the diversemethods available for use in making the disclosed compounds and is notintended to limit the scope of reactions or reaction sequences that canbe used in preparing the compounds provided herein. The skilled artisanwill understand that standard atom valencies apply to all compoundsdisclosed herein in genus or named compound for unless otherwisespecified.

All final compounds of the examples described herein were checked forpurity by HPLC on a Shimadzu LC-2010A and compounds were detected at thewavelength of 214 nM and 254 nM. Purities for all final compounds wereover 95% based on HPLC peaks (214 nM and 254 nM wavelength). Liquidchromatography condition: Column, XBRIDGE C18, 3.6 micron, 2.1×50 mm:Mobile phase, water (0.05% TFA) and acetonitrile (0.05% TFA), lineargradient from 10% acetonitrile to 100% acetonitrile over 7 min; Oventemperature 45° C.; Flow rate, 0.8 mL/mL. H-NMR was obtained on Bruker400 MHz NMR spectrometer.

General Synthetic Schemes

Compounds of Formula (1) (e.g. Formula (1A); see compounds in Table 2)can be prepared according to the following schemes. The followingschemes represent the general methods used in preparing these compounds.However, the synthesis of these compounds is not limited to theserepresentative methods, as they can also be prepared by various othermethods those skilled in the art of synthetic chemistry, for example, ina stepwise or modular fashion.

Compound 3-2 can be synthesized according to the similar method asdescribed in Scheme 1.

Compounds 3-3, 3-4, and 3-5 can be prepared according to the similarmethod as described in Scheme 2.

Compounds 3-14, 3-15, 3-16, 3-17, 3-18, 3-19, and 3-27 can besynthesized with similar method as described in Scheme 4.

Compounds 3-20, 3-21, 3-23, 32-24, 3-25, 3-26 and 3-28 can be preparedusing the similar synthetic route.

The following compounds can be synthesized according to similarsynthetic method as described in Scheme 6: 3-29, 3-30, 3-32, 3-33, 3-34,3-47 and 3-48.

The following compounds can be synthesized according to similarsynthetic method as described in Scheme 7: 3-8, 3-9, 3-10, 3-12 and3-43.

Compounds 3-36, 3-49, 3-50, 3-51 and 3-52 can be synthesized using thesame method.

Compounds 3-38, 3-39 and 3-40 can be prepared using the same routedescribed in Scheme 9.

Compounds 3-42, 3-45 and 3-46 can be synthesized using the same method.

Preparation of Intermediates Synthesis oftrans-5-(4-aminocyclohexyl)oxyquinoline-8-carbonitrile Hydrochloride(Intermediate 1)

Step 1: Preparation of 5-fluoroquinoline-8-carbonitrile

A mixture containing 8-bromo-5-fluoroquinoline (2.00 g, 8.85 mmol, 1.00eq), Pd(PPh₃)₄ (1.02 g, 884.7 umol, 0.10 eq) and Zn(CN)₂ (2.01 g, 17.1mmol, 1.08 mL, 1.93 eq) was taken up into a microwave tube in DMF (20.0mL). The sealed tube was heated at 150° C. for 0.5 h under microwavecondition. TLC (petroleum ether/ethyl acetate=3/1, R_(f) (startingmaterial)=0.50, R_(f) (product)=0.32) showed the starting material wasconsumed completely. Four reactions were repeated in parallel and theresulting reactions were combined for workup. The mixture was pouredinto water (300.0 mL), extracted with EtOAc (80.0 mL×2). The combinedorganic layers were washed with brine (150.0 mL), dried over Na₂SO₄,filtered and concentrated under reduce pressure to give a residue. Thecrude product was purified by column chromatography on silica gel elutedwith petroleum ether/ethyl acetate (50/1 to 1/1) to provide the titlecompound (3.20 g, 52.1% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃)δ 9.18 (dd, J=4.44, 1.65 Hz, 1H), 8.52 (dd, J=8.40, 1.65 Hz, 1H), 8.14(dd, J=8.40, 5.51 Hz, 1H), 7.64 (dd, J=8.44, 4.30 Hz, 1H), 7.32 (t,J=8.40 Hz, 1H).

Step 2: Preparation of Tert-Butyltrans-4-((8-cyanoquinolin-5-yl)oxy)cyclohexylcarbamate

To a mixture of 5-fluoroquinoline-8-carbonitrile (1.50 g, 8.71 mmol,1.00 eq) and tert-butyl trans-4-hydroxycyclohexyl)carbamate (1.88 g,8.71 mmol, 1.00 eq) in ACN (10.0 mL) was added Cs₂CO₃ (5.68 g, 17.4mmol, 2.00 eq) in one portion at 15° C. under N₂. The mixture wasstirred at 80° C. for 2 h. TLC (petroleum ether:ethyl acetate=1:1, R_(f)(starting material)=0.65, R_(f) (product)=0.47) showed the startingmaterial was consumed completely. The mixture was filtered and the cakewas washed with EtOAc (30.0 mL). The combined organic layers wereconcentrated in vacuum. The crude product was purified by columnchromatography on silica gel eluted with petroleum ether/ethyl acetate(30:1 to 1:1) to provide the title compound (1.90 g, 59.4% yield) as ayellow solid.

Step 3: Preparation oftrans-5-((4-aminocyclohexyl)oxy)quinoline-8-carbonitrile Hydrochloride(Intermediate 1)

To a solution of tert-butyltrans-4-((8-cyanoquinolin-5-yl)oxy)cyclohexylcarbamate (1.90 g, 5.17mmol, 1.00 eq) in DCM (5.00 mL) was added HCl (g)/EtOAc (4.00 M, 20.0mL, 15.4 eq) at 0° C. for 0.5 h. TLC (petroleum ethyl/ether acetate=1/1,R_(f) (starting material)=0.54, R_(f) (product)=0) showed the startingmaterial was consumed completely. The mixture was filtered and the cakewas washed with DCM (10.0 mL), dried in vacuum to provide the titlecompound (1.06 g, 3.40 mmol, 65.7% yield, 97.5% purity, HCl salt) as ayellow solid. LC/MS: 268.1 (M+H)+; ¹H NMR: ET26887-10-P1A (400 MHz,MeOD) δ 9.14-9.18 (m, 2H), 8.40 (d, J=8.48 Hz, 1H), 7.92-7.97 (m, 1H),7.47 (d, J=8.44 Hz, 1H), 4.81-4.87 (m, 1H), 3.24-3.30 (m, 1H), 2.37-2.46(m, 2H), 2.21 (br d, J=12.44 Hz, 2H), 1.67-1.87 (m, 4H).

Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione(Intermediate 2-1)

Intermediate 2-1 was prepared according to the above scheme as ahydrochloride salt using a similar method described in the literature.LC/MS 343.1 [M+H]⁺; ¹H-NMR (400 MHz, CD₃OD) δ ppm 7.76 (d, J=8.36 Hz,1H), 7.47 (s, 1H), 7.35 (dd, J=8.36, 1.54 Hz, 1H), 5.09 (br dd, J=12.8,5.40 Hz, 1H), 3.67-3.74 (m, 4H), 3.37-3.42 (m, 4H), 2.63-2.94 (m, 3H),2.07-2.17 (m, 1H).

Synthesis of(S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione(Intermediate 2-2)

To a solution of (S)-tert-butyl4-(2-(1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate(5.8 g, 12 mol, prepared according to the same method as described inIntermediate 2-4 synthesis) in acetonitrile (90 mL) was addedbenzenesulfonic acid (3.64 g, 23 mol). The mixture was stirred at 85° C.for 12 h. LC/MS showed the reaction was complete. The mixture wasconcentrated in vacuum. The residue was triturated with ethyl acetate toafford(S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dionebenzenesulfonate (5.2 g, 93%) as off-white solid. LC/MS 329.1 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d6) δ 1.95-1.99 (m, 1H), 2.36-2.41 (m, 1H), 2.58-2.62(d, 1H), 2.88-2.91 (m, 1H), 3.26 (s, 4H), 3.49-3.52 (m, 4H), 4.21-4.38(dd, 2H), 5.05-5.10 (dd, 1H), 7.12-7.16 (m, 2H), 7.30-7.358 (m, 3H),7.58-7.62 (m, 3H), 8.72 (s, 2H).

Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione(Intermediate 2-3)

Intermediate 2-3 was prepared according to the above scheme as ahydrochloride salt. LC/MS 361.1 [M+1]±; ¹H NMR (400 MHz, DMSO-d6) δ 11.1(s, 1H), 9.49 (br s, 2H), 7.79 (d, J=11.2 Hz, 1H), 7.57 (br d, J=7.32Hz, 1H), 5.12 (br dd, J=12.4, 5.32 Hz, 1H), 3.50 (br s, 4H), 3.24 (br s,4H), 2.80-2.95 (m, 1H), 2.52-2.69 (m, 2H), 1.97-2.10 (m, 1H).

Synthesis of(S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione(Intermediate 2-4)

Step 1: Preparation of methyl 2-bromo-4,5-difluorobenzoate

Thionyl chloride (130 g, 1.09 mol) was added slowly to a mixture of2-bromo-4,5-difluorobenzoic acid (200 g, 0.84 mol) in MeOH (600 mL) at10° C., the mixture was stirred at 80° C. for 3 h. TLC showed thereaction was completed. The mixture was cooled to room temperature,concentrated, then partitioned between ethyl acetate and water. Theorganic layer was washed with saturated Na₂CO₃ and brine twice, driedover Na₂SO₄ and concentrated to afford a crude methyl2-bromo-4,5-difluorobenzoate (210 g, yield: 100%) which was used for thenext step without further purification.

Step 2: Preparation of tert-butyl4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl) piperazine-1-carboxylate

A mixture of methyl 2-bromo-4,5-difluorobenzoate (210 g, 0.84 mol),tert-butyl piperazine-1-carboxylate (234 g, 1.25 mol) and K₂CO₃ (173 g,1.25 mol) in N,N-dimethylacetamide (600 mL) was stirred at 80° C. for 16h. TLC showed the reaction was completed. The mixture was added to water(2 L) and stirred for 10 min followed by the addition of ethyl acetate.The mixture was partitioned between ethyl acetate and water. The organiclayer was washed with water, brine, dried over Na₂SO₄ and concentratedto afford tert-butyl4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(315.8 g, yield: 90%).

Step 3: Preparation of tert-butyl4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl) piperazine-1-carboxylate

A mixture of tert-butyl4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(306 g, 0.73 mol) and CuCN (98 g, 1.09 mol) in DMF (1.2 L) was stirredat 100° C. for 16 h. TLC showed the reaction was completed. The mixturewas cooled to room temperature. Ethyl acetate (2 L) and ammoniumhydroxide (2 L) were added and the mixture was stirred for 30 min. Themixture was filtered. The organic layer was washed with water, driedover Na₂SO₄ and concentrated to afford a crude product (254 g). Thiscrude product was taken into petroleum ether (1 L) at reflux. Themixture was filtered and dried in oven at 50° C. to afford tert-butyl4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(215 g, yield: 81%).

Step 4: Preparation of tert-butyl4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl) piperazine-1-carboxylate

To a solution of pyridine (391 g, 4.95 mol), water (200 mL), acetic acid(264 g, 4.4 mol) was added tert-butyl4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(200 g, 0.55 mol) and Raney-nickel (85% in water, 100 g) at roomtemperature. The resulting mixture was heated to 60° C. Sodiumhypophosphite (292 g in 500 mL water) was added dropwise into themixture. The mixture was stirred for 16 h at 60° C. TLC showed thereaction not completed. The mixture was further stirred for 10 h. Themixture was cooled to room temperature. Ethyl acetate and water wereadded. The mixture was filtered. The organic layer was washed withwater, 1N HCl and brine, dried over Na₂SO₄ and concentrated underreduced pressure to afford a crude product (208 g, crude) which wasfurther purified by silica-gel pad to provide4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(86.5 g, yield: 43%).

Step 5: Preparation of tert-butyl(S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(81.5 g, 0.22 mol) in methanol (500 mL) was added tert-butyl(S)-4,5-diamino-5-oxopentanoate (54 g, 0.27 mol) at room temperature.Acetic acid (19.8 g, 0.33 mol) was added at 0° C. followed by theaddition of sodium cyanoborohydride (27.6 g, 0.44 mol) slowly. Themixture was stirred at room temperature for 16 hours. TLC showed thereaction was completed. The mixture was concentrated and partitionedbetween ethyl acetate and water. The organic layer was washed withsaturated citric acid, brine, dried over Na₂SO₄ and concentrated underreduced pressure to afford a crude product which was further purified bysilica-gel pad to give tert-butyl(S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate(80 g, yield: 69%).

Step 6: Preparation of(S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dioneBenzenesulfonic Acid (Intermediate 2-4)

To a solution of(S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate(67 g, 0.13 mol) in acetonitrile (670 mL) was added benzenesulfonic acid(43 g, 0.26 mol). The mixture was stirred at 80° C. for 16 h. LCMSshowed the reaction was complete. The mixture was cooled to roomtemperature. The mixture was filtered and dried to afford(S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dionebenzenesulfonic acid (56 g, 86%) as off-white solid. ¹H NMR (400 MHz,DMSO-d6) δ 1.94-1.99 (m, 1H), 2.35-2.43 (m, 1H), 2.58-2.62 (m, 1H),2.88-2.91 (m, 1H), 3.30 (br s, 8H), 4.38 (d, J=17.2 Hz, 1H), 4.26 (d,J=17.2 Hz, 1H), 5.08 (dd, J=13.2, 5.2 Hz, 1H), 7.29-7.35 (m, 4H), 7.49(d, J=8.7 Hz, 1H), 7.60 (m, 2H), 8.72 (br s, 2H), 10.99 (s, 1H). LCMSm/z 347.3 [M+1]⁺.

Preparation of Example Compounds

All final compounds of examples described in this section and in Table 2were checked for purity by HPLC and compounds were detected at thewavelength of 214 nM and 254 nM. Purities for all final compounds wereover 95% based on HPLC peak analysis (214 nM and 254 nM wavelength).H-NMR was obtained on Bruker NMR spectrometer (400 MHz). LC/MS wasperformed on Agilent 6125 under the following condition: column, WatersCORTECS C18, 27 um, 4.6×30 mm; mobile phase, ACN (0.05% TFA) and water(0.05 TFA); gradient: 5% ACN to 95% ACN in 1.0 min, hold 1.0 min, total2.5 min; flow rate 1.8 mL/min; column temperature 45° C. Analytical HPLCwas performed on SHIMADZU LC-2010A under the following conditions:column, XBRIDGE 3.5 um, 2.1×50 mm; mobile phase, water (0.05% TFA) andACN (0.05% TFA); gradient, ACN from 10% to 100% over 7 minutes, hold 1min; column oven temperature, 45° C.; flow rate, 0.8 ml/min.

Synthesis oftrans-N-(4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide(3-13)

Step 1: Preparation of tert-butyl6-(4-(hydroxymethyl)piperidin-1-yl)nicotinate

A mixture of tert-butyl 6-chloronicotinate (500 mg, 2.35 mmol),piperidin-4-ylmethanol (297 mg, 2.58 mmol) and DIEA (606 mg, 4.70 mmol)in DMSO (10 mL) was stirred at 100° C. overnight. TLC showed thereaction completed. The mixture was partitioned between EA and H₂O. Theorganic phase was washed with brine, dried over magnesium sulfate andevaporated to dryness. The crude product was purified by silica gelchromatography (10-50% EtOAc in hexane as eluent) to afford the desiredcompound (400 mg, 58.3%). LC/MS: 293.2 [M+H]⁺.

Step 2: Preparation of tert-butyl 6-(4-formylpiperidin-1-yl)nicotinate

A mixture of tert-butyl 6-(4-(hydroxymethyl)piperidin-1-yl)nicotinate(574 mg, 1.97 mmol) and IBX (658 mg, 2.35 mmol) in DMSO (10 mL) wasstirred at 50° C. overnight. TLC showed the reaction completed. Themixture was partitioned between EA and H₂O. The organic phase was washedwith brine, dried over magnesium sulfate and evaporated to dryness. Thecrude product was purified by silica gel chromatography with 10-50%EtOAc in hexane as eluent to afford the desired compound (400 mg, 70%).LC/MS: 291.0 [M+H]⁺.

Step 3: Preparation of tert-butyl6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinate

To a solution of tert-butyl 6-(4-formylpiperidin-1-yl)nicotinate (200mg, 0.69 mmol), intermediate 2-1 (260 mg, 0.68 mmol), MgSO₄ (820 mg, 6.8mmol) in dichloromethane (10 mL) was added Et₃N (140 mg, 1.36 mmol). Themixture was stirred at room temperature for 1 hour. Then the sodiumtriacetoxyborohydride (430 mg, 2.04 mmol) was added slowly to themixture. The mixture was stirred at room temperature overnight. Theresidue was concentrated in vacuum. The crude product was purified bysilica gel chromatography using 5-10% MeOH in DCM as eluent to affordthe desired compound (250 mg, 59%). LC/MS: 617.3 [M+H]⁺.

Step 4: Preparation of6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinicAcid

To a solution of tert-butyl6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinate(230 mg, 0.37 mmol) in dichloromethane (10 mL) was added TFA (2 mL). Themixture was stirred at room temperature for overnight. The residue wasconcentrated in vacuum. The crude product was used in next step withoutfurther purification. LC/MS: 561.1 [M+H]⁺.

Step 5: Preparation oftrans-N-(4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide(3-13)

A solution of6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinicacid (130 mg, crude), Intermediate 1 (84 mg, 0.28 mmol), HATU (105 mg,0.27 mmol) and DIEA (200 mg, 1.55 mmol) in DMF (7 mL) was stirred atroom temperature overnight. TLC showed the reaction completed. Themixture was partitioned between EA and H₂O. The organic phase was washedwith brine, dried over magnesium sulfate and evaporated to dryness. Thecrude product was purified by preparative TLC (MeOH:DCM=1:15) to affordthe desired compound (54 mg, 24%). LC/MS: 810.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO) δ 11.10 (s, 1H), 9.08 (dd, J=4.2, 1.7 Hz, 1H), 8.68-8.59 (m, 2H),8.31 (t, J=7.2 Hz, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.96 (dd, J=9.0, 2.4 Hz,1H), 7.70 (dd, J=8.5, 4.5 Hz, 2H), 7.37 (d, J=8.6 Hz, 2H), 7.27 (d,J=8.7 Hz, 1H), 6.84 (d, J=9.1 Hz, 1H), 5.08 (dd, J=12.8, 5.4 Hz, 1H),4.75 (m, 1H), 4.41 (d, J=13.1 Hz, 2H), 3.88 (m, 1H), 3.45 (br s, 4H),3.32 (br s, 1H), 2.96-2.83 (m, 4H), 2.70-2.45 (m, 4H), 2.35-2.15 (m,4H), 2.08-1.91 (m, 3H), 1.89-1.77 (m, 3H), 1.69-1.55 (m, 4H), 1.30-1.10(m, 2H).

Synthesis oftrans-N-(4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide(3-15)

Step 1: Preparation of tert-butyl 2-chloropyrimidine-5-carboxylate

A mixture of 2-chloropyrimidine-5-carboxylic acid (2 g, 12.6 mmol), DMAP(154 mg, 1.26 mmol) and Boc₂O (5.5 g, 25.2 mmol) in t-BuOH (10 mL) wasstirred at 50° C. overnight. TLC showed the reaction completed. Theorganic phase was evaporated to dryness. The crude product was purifiedby silica gel chromatography (10-70% EtOAc in hexane as eluent) toafford the desired compound (800 mg, 29%). LC/MS: 215.2 [M+H]⁺.

Step 2 through Step 6 were performed according to the same procedure asdescribed in the preparation of 3-13.

The desired compound 3-15 was obtained following preparative TLC(MeOH:DCM=1:20). LC/MS: 811.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 11.12 (s,1H), 9.08 (dd, J=4.1, 1.3 Hz, 1H), 8.80 (s, 2H), 8.69-8.61 (m, 1H), 8.31(d, J=8.3 Hz, 1H), 8.19 (d, J=7.5 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.70(dd, J=8.6, 4.3 Hz, 1H), 7.52 (s, 1H), 7.38 (t, J=7.4 Hz, 2H), 5.11 (dd,J=12.8, 5.4 Hz, 1H), 4.76 (br d, J=13.0 Hz, 2H), 4.23 (br d, J=12.1 Hz,3H), 3.88 (m, 1H), 3.40-3.27 (m, 2H), 3.27-2.95 (m, 6H), 2.97-2.82 (m,1H), 2.70-2.53 (m, 2H), 2.45-2.14 (m, 4H), 2.13-1.92 (m, 3H), 1.91-1.79(m, 3H), 1.73-1.51 (m, 4H), 1.35-1.06 (m, 2H).

Synthesis oftrans-N-(4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide(3-16)

This compound was prepared using the same method as described for 3-13except that tert-butyl 6-chloropyridazine-3-carboxylate was used. Thefinal crude product was purified by preparative TLC to afford thedesired compound (60 mg, 27%). LC/MS: 810.7 [M+H]⁺; ¹H NMR (300 MHz,DMSO) δ 11.04 (s, 1H), 9.03 (dd, J=4.2, 1.7 Hz, 1H), 8.65-8.55 (m, 2H),8.25 (d, J=8.3 Hz, 1H), 7.78 (d, J=9.6 Hz, 1H), 7.66 (dd, J=8.4, 4.3 Hz,2H), 7.36-7.28 (m, 3H), 7.29-7.19 (m, 1H), 5.10-4.99 (m, 1H), 4.80-4.62(m, 1H), 4.56-4.39 (m, 2H), 3.99-3.83 (m, 1H), 3.43 (br s, 4H), 3.28 (brs, 1H), 3.08-2.96 (m, 2H), 2.88-2.79 (m, 1H), 2.75-2.67 (m, 1H),2.62-2.45 (m, 4H), 2.27-2.18 (m, 4H), 1.97-1.79 (m, 6H), 1.73-1.60 (m,4H), 1.20-1.08 (m, 2H).

Synthesis ofN-(4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide(3-18)

This compound was prepared using the same method as described for thepreparation of 3-13 except that tert-butyl 4-fluorobenzoate was used.The final crude product was purified by preparative TLC withMeOH:DCM=1:10 to afford the desired compound (37 mg, 36%). LC/MS: 809.3[M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.08 (dd, J=4.2, 1.7 Hz,1H), 8.65 (dd, J=8.5, 1.7 Hz, 1H), 8.30 (d, J=8.3 Hz, 1H), 8.01 (d,J=7.6 Hz, 1H), 7.79-7.66 (m, 3H), 7.37 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.6Hz, 1H), 6.95 (d, J=9.1 Hz, 2H), 5.08 (dd, J=13.0, 5.4 Hz, 1H), 4.74 (m,1H), 3.86 (m, 3H), 3.46 (br s, 4H), 3.31 (br s, 1H), 2.84 (dt, J=24.2,11.9 Hz, 2H), 2.77 (t, J=11.3 Hz, 2H), 2.65-2.50 (m, 4H), 2.36-2.17 (m,4H), 2.08-1.89 (m, 3H), 1.82 (d, J=12.4 Hz, 3H), 1.74-1.52 (m, 4H),1.28-1.10 (m, 2H).

Synthesis ofN-(4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide(3-19)

This compound was prepared using the similar method as described in thesynthesis of 3-13. The final crude product was purified by prep-H PLC togive the title compound (60 mg, 42%). LC/MS: 826.7 [M+H]⁺; ¹H NMR (400MHz, DMSO) δ 11.10 (s, 1H), 9.08 (dd, J=4.2, 1.7 Hz, 1H), 8.65 (dd,J=8.5, 1.6 Hz, 1H), 8.30 (d, J=8.3 Hz, 1H), 8.20 (d, J=7.5 Hz, 1H), 7.68(ddd, J=18.0, 11.1, 5.5 Hz, 4H), 7.37 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.6Hz, 1H), 7.08 (t, J=8.9 Hz, 1H), 5.09 (dd, J=12.8, 5.3 Hz, 1H), 4.75 (m,1H), 3.88 (m, 1H), 3.60-3.40 (br s, 6H), 2.96-2.82 (m, 1H), 2.75 (t,J=11.3 Hz, 2H), 2.67-2.52 (m, 6H), 2.41-2.20 (m, 4H), 2.08-1.90 (m, 3H),1.84 (d, J=12.8 Hz, 2H), 1.80-1.51 (m, 5H), 1.36-1.24 (m, 2H).

Synthesis oftrans-N-(4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide(3-31)

Step 1: Preparation of tert-butyl(S)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzoate

To a solution of tert-butyl 3-fluoro-4-(4-formylpiperidin-1-yl)benzoate(31 mg, 0.1 mmol) and intermediate 2-2 (48.6 mg, 0.1 mmol) in DCM (2 mL)stirred under nitrogen at room temperature was added magnesium sulphate(240 mg, 2 mmol) and triethylamine (20 mg, 0.2 mmol). The reactionmixture was stirred at room temperature for 1 hour. Then NaBH(OAc)₃ (53mg, 0.25 mmol) was added in portions. The reaction was stirred for 1hour. The solvent was removed in vacuum to give a crude product whichwas purified by silica gel column chromatography (eluted with 0-15% MeOHin DCM) to give the title compound (60 mg, 96%). LC/MS: 619.8 [M+H]⁺.

Step 2: Preparation of(S)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzoicAcid

To the solution of(S)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzoate(60 mg, 0.09 mmol) in DCM (2 mL) was added TFA (0.4 mL). The reactionwas stirred for 16 hours. The solvent was removed in vacuum to give theproduct (55 mg, 100%). LC/MS: 563.7 [M+H]⁺.

Step 3: Preparation oftrans-N-(4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide(3-31)

This step of amide formation was performed using the same procedure asdescribed in the last step (step 5) of the synthesis of 3-13. LC/MS:812.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.08 (dd, J=4.2,1.7 Hz, 1H), 8.65 (dd, J=8.5, 1.6 Hz, 1H), 8.30 (d, J=8.3 Hz, 1H), 8.23(br d, J=8.1 Hz, 1H), 7.69-7.65 (m, 3H), 7.51-7.62 (m, 1H), 7.36 (d,J=8.2 Hz, 1H), 7.04-7.23 (m, 3H), 5.06 (dd, J=13.2, 5.0 Hz, 1H), 4.75(m, 1H), 4.35 (d, J=12.2 Hz, 1H), 4.23 (d, J=12.2 Hz, 1H), 3.90-3.80 (m,1H), 3.49 (br d, J=8. Hz, 2H), 3.30-3.27 (br, 4H), 2.93-2.82 (m, 1H),2.80-2.70 (m, 2H), 2.68-2.50 (m, 5H), 2.40-2.19 (m, 5H), 1.97 (m, 3H),1.86-1.75 (m, 3H), 1.73-1.57 (m, 4H), 1.35-1.15 (m, 2H).

Synthesis oftrans-N-(4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide(3-29)

Compound 3-29 was prepared using the similar method as for thepreparation of 3-31. The final crude product was purified by prep-TLC(DCM:MeOH=15:1) to afford the desired product as a yellow solid. (23.1mg, 20.1%). LC/MS: 795.7 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 10.96 (s, 1H),9.07 (dd, J=4.2, 1.7 Hz, 1H), 8.68-8.58 (m, 2H), 8.29 (d, J=8.3 Hz, 1H),8.08 (d, J=7.0 Hz, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.69 (dd, J=8.5, 4.2 Hz,1H), 7.54 (s, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.09 (br s, 2H), 6.88-6.80(m, 1H), 5.05 (dd, J=13.1, 4.8 Hz, 1H), 4.78-4.70 (m, 1H), 4.44-4.30 (m,3H), 4.21 (d, J=12.3 Hz, 1H), 3.86 (m, 1H), 3.64-3.56 (m, 1H), 3.35-3.25(m, 5H, overlap with DMSO-d6), 3.17-3.10 (m, 1H), 3.01-2.81 (m, 4H),2.65-2.58 (m, 1H), 2.44-2.17 (m, 5H), 2.00-1.92 (m, 3H), 1.87-1.76 (m,3H), 1.70-1.53 (m, 4H), 1.30-1.00 (m, 2H).

Synthesis oftrans-N-(4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzamide(3-22)

Step 1: Preparation of tert-butyl4-(4-(2-hydroxyethyl)piperidin-1-yl)benzoate

A solution of tert-butyl 4-fluorobenzoate (200 mg 1.02 mmol),2-(piperidin-4-yl)ethanol (131.6 mg 1.02 mmol), potassium carbonate(422.6 mg 3.06 mmol) in DMF (5 mL) was stirred under nitrogen at 100° C.for 18 hours. The reaction mixture was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(MeOH:dichloromethane=1:10) to afford the target compound (210 mg, 0.69mmol, 67% yield) as white solid. LC/MS: 306 [M+H]⁺.

Step 2: Preparation of tert-butyl4-(4-(2-oxoethyl)piperidin-1-yl)benzoate

A mixture of tert-butyl 4-[4-(2-hydroxyethyl)piperidin-1-yl]benzoate(200 mg, 0.69 mmol) and IBX (218.42 mg 0.78 mmol) in DMSO (4 mL) wasstirred at 50° C. under nitrogen for 18 hours. The reaction mixture wastreated with 20 mL of water and extracted with EtOAc (3×5 mL). Thecombined organic phase was washed with water (5 mL), dried over MgSO₄and concentrated in vacuo. The residue was purified by silica gel columnchromatography (EA:dichloromethane=1:5) to afford the target compound(150 mg, 0.49 mmol, 72% yield) as a grey solid. LC/MS: 304.0 [M+H]⁺.

Step 3: Preparation of tert-butyl4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzoate

To a mixture of tert-butyl 4-[4-(2-oxoethyl)piperidin-1-yl]benzoate (150mg, 0.49 mmol), DIPEA (63.9 mg, 0.49 mmol), Intermediate 2-1 (187.4 mg,0.49 mmol) and MgSO₄ (300 mg) in dichloromethane (3 mL) was addedNaHB(OAc)₃ (314.4 mg, 1.48 mmol). The mixture was stirred at 25° C. for18 hours. The residue was diluted with water (50 mL) and extracted withdichloromethane (50 mL×3). The combined organic layers were dried withanhydrous sodium sulfate, filtered and concentrated in vacuum. Theresidue was purified by reverse phase preparative HPLC to give thedesired compound as a yellow solid (240 mg, 0.38 mmol, 78% yield).LC/MS: 630.3 [M+H]⁺.

Step 4: Preparation of4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzoicAcid

A mixture of tert-butyl4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzoate(240 mg, 0.38 mmol) in DCM (5 mL) and TFA (0.5 mL) was stirred at 25° C.for 18 hours. The reaction mixture was concentrated under reducedpressure to afford the target compound (220 mg, 0.38 mmol, 100% yield)as yellow solid. LC/MS: 574.2 [M+H]⁺.

Step 5: Preparation oftrans-N-(4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzamide(3-22)

To a mixture of4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzoicacid (100 mg, 0.17 mmol), Intermediate 1 (53.04 mg, 0.17 mmol), DIEA(90.21 mg, 0.70 mmol), in DMF (1 mL) was added HATU (86.3 mg, 0.23 mmol)portion-wise. The resulting mixture was stirred at 25° C. for 18 hours.The reaction mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(NH₃:MeOH:dichloromethane=1:10:100) to afford the target molecule (50mg, 0.06 mmol, 35% yield) as a brown solid. LC/MS: 823.2 [M+H]⁺; ¹H NMR(400 MHz, DMSO) δ 11.10 (s, 1H), 9.08 (dd, J=4.2, 1.7 Hz, 1H), 8.65 (dd,J=8.5, 1.6 Hz, 1H), 8.30 (d, J=8.3 Hz, 1H), 8.00 (d, J=7.6 Hz, 1H),7.82-7.63 (m, 4H), 7.36 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.6 Hz, 1H), 6.94(d, J=9.0 Hz, 2H), 5.08 (dd, J=12.9, 5.4 Hz, 1H), 4.80-4.68 (m, 1H),3.96-3.74 (m, 3H), 3.70-3.53 (m, 1H), 3.53-3.37 (m, 3H), 3.21-3.08 (m,1H), 2.97-2.80 (m, 1H), 2.80-2.64 (m, 2H), 2.64-2.54 (m, 2H), 2.48-2.30(m, 5H), 2.30-2.19 (m, 2H), 2.11-1.89 (m, 3H), 1.85-1.39 (m, 9H),1.35-1.15 (m, 2H).

Testing of Compounds for AR Degradation Activity

LNCAP, VCAP and 22Rv1 cells were plated in 24-well plates at 1.5×10E5cells/well in the RPMI growth medium containing 10% FBS and 1%Penicillin Streptomycin, and then incubated at 37° C. overnight. Thefollowing day, the test compound was administered to the cells by using1000× compound stock solution prepared in DMSO at variousconcentrations. After administration of the compound, the cells werethen incubated at 37° C. for 24 hours. Upon completion, the cells werewashed with PBS and protein was collected in Laemmli sample buffer (1×;VWR International). Proteins in cell lysate were separated by SDS-PAGEand transferred to Odyssey nitrocellulose membranes (Licor) with Iblot®dry blotting transfer system (ThermoFisher). Nonspecific binding wasblocked by incubating membranes with Intercept Blocking Buffer (Licor)for 1 hour at room temperature with gentle shaking. The membranes werethen incubated overnight at 4° C. with Primary antibodies rabbit anti-AR(1:1,000, Cell Signaling, 5153) and mouse anti-GAPDH (1:5,000, SantaCruz Biotechnology, sc-47724) diluted in Intercept Blocking Buffercontaining 0.1% Tween 20. After washing 3 times with TBS-T, themembranes were incubated with IRDye® 800CW goat anti-mouse IgG(1:20,000, Licor) or IRDye® 800CW goat anti-rabbit IgG (1:20,000, Licor)for 1 hour. After TBS-T washes, membranes were rinsed in TBS and scannedon Odyssey® CLx Imaging System (Licor). The bands were quantified usingImage Studio™ Software (Licor).

Table 4 summarizes the androgen receptor (AR) degradative activity ofexemplary compounds in LNCAP, VCAP and 22Rv1 cell lines 24 hours afteradministration. DC50: compound concentration needed for 50% targetprotein degradation.

TABLE 4 AR degradative activity of compounds from cellular assays (A:DC50 < 10 nM; B: DC50 > 100 nM) Com- LNCAP VCAP 22RV1 pounds (DC50, nM)(DC50, nM) (DC50, nM) 3-22 A A N/A 3-18 A A N/A 3-16 A A N/A 3-13 A AN/A 3-15 A A N/A 3-19 A A N/A 3-29 A A A 3-49 B N/A N/A 3-31 A A A 3-35A N/A N/A 3-50 A N/A N/A 3-51 A N/A N/A 3-30 A A N/A 3-36 A A A 3-53 AN/A N/A 3-9 A N/A N/A 3-11 A N/A N/A 3-43 A N/A N/A 3-17 A N/A N/A 3-52A N/A N/A 3-54 A N/A N/A 3-55 A N/A N/A

The many features and advantages of the present disclosure are apparentfrom the detailed specification, and thus it is intended by the appendedclaims to cover all such features and advantages of the presentdisclosure that fall within the true spirit and scope of the presentdisclosure. Further, since numerous modifications and variations willreadily occur to those skilled in the art, it is not desired to limitthe present disclosure to the exact construction and operationillustrated and described and accordingly, all suitable modificationsand equivalents may be resorted to, falling within the scope of thepresent disclosure.

Moreover, those skilled in the art will appreciate that the conceptionupon which this disclosure is based may readily be used as a basis fordesigning other structures, methods, and systems for carrying out theseveral purposes of the present disclosure. Accordingly, the claims arenot to be considered as limited by the foregoing description orexamples.

1-83. (canceled)
 84. A compound of Formula (1) or a pharmaceuticallyacceptable salt thereof:

wherein: X₁ is CR₁ or N; X₂ is CR₂ or N; X₃ is CR₃ or N; X₄ is CR₄ or N;each of R₁, R₂, R₃, and R₄ is independently selected from hydrogen,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkyl, each of which is substitutedwith 0, 1, 2, or 3 R_(S); each R₅ is independently selected fromhalogen, hydroxyl, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and—CN, each of which is substituted with 0, 1, 2, or 3 R_(S); each R₆ isindependently selected from hydrogen, halogen, C₁-C₃alkyl, andC₁-C₃haloalkyl, each of which is substituted with 0, 1, 2, or 3 R_(S),or two R₆ groups are taken together to form an oxo; each R₇ isindependently selected from halogen, hydroxyl, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃haloalkyl, —N(R₉)₂, and —CN, each of which is substituted with 0,1, 2, or 3 R_(S); each R₈ is independently selected from hydrogen,hydroxyl, C₁-C₃alkyl, and C₁-C₃haloalkyl, each of which is substitutedwith 0, 1, 2, or 3 R_(S), or two R₈ groups are taken together to form anoxo; each R₉ is independently selected from hydrogen, C₁-C₃alkyl,—C(═O)—(C₁-C₃alkyl), —C(═O)—O—(C₁-C₃alkyl), and —C(═O)—NH—(C₁-C₃alkyl),each of which is substituted with 0, 1, 2, or 3 R_(S), or two R₉ groupsare taken together to form a 3- to 6-membered heterocycle or heteroaryl;each R_(S) is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN; L is a linker of 1 to 16carbon atoms in length, wherein one or more carbon atoms are optionallyreplaced by C(O), O, N(R₉), S, C₂-alkenyl, C₂-alkynyl, cycloalkyl, aryl,heterocycle, or heteroaryl, wherein the R₉, C₂-alkenyl, cycloalkyl,aryl, heterocycle, and heteroaryl are each independently substitutedwith 0, 1, 2, or 3 R_(S); m is 0, 1, or 2; n is 0, 1, 2, or 3; and o is0, 1, 2, or 3, wherein each hydrogen atom is independently andoptionally replaced by a deuterium atom.
 85. The compound orpharmaceutically acceptable salt thereof according to claim 84, whereinX₂ is CR₂, X₃ is CR₃, and X₄ is CR₄.
 86. The compound orpharmaceutically acceptable salt thereof according to claim 85, whereinR₂, R₃, and R₄ are each independently selected from H and F.
 87. Thecompound or pharmaceutically acceptable salt thereof according to claim84, wherein X₁ is CR₁, X₂ is CR₂, X₃ is CR₃, and X₄ is CR₄.
 88. Thecompound or pharmaceutically acceptable salt thereof according to claim87, wherein R₁, R₂, R₃, and R₄ are each independently selected from Hand F.
 89. The compound or pharmaceutically acceptable salt thereofaccording to claim 84, wherein the

group is selected from


90. The compound or pharmaceutically acceptable salt thereof accordingto claim 84, wherein each R₅ is independently selected from halogen,C₁-C₃alkoxy, and C₁-C₃haloalkyl.
 91. The compound or pharmaceuticallyacceptable salt thereof according to claim 90, wherein each R₅ isindependently selected from —Cl, —OCH₃, and —CF₃.
 92. The compound orpharmaceutically acceptable salt thereof according to claim 84, whereinm is 0 or
 1. 93. The compound or pharmaceutically acceptable saltaccording to claim 84, wherein o is 0 or
 1. 94. The compound orpharmaceutically acceptable salt thereof according to claim 84, whereineach R₆ is independently selected from H and C₁-C₃alkyl.
 95. Thecompound or pharmaceutically acceptable salt thereof according to claim84, wherein each R₆ is independently selected from H and —CH₃.
 96. Thecompound or pharmaceutically acceptable salt thereof according to claim84, wherein the two R₆ groups attached to the same carbon are identical.97. The compound or pharmaceutically acceptable salt thereof accordingto claim 84, wherein the

group is selected from


98. The compound or pharmaceutically acceptable salt thereof accordingto claim 84, wherein the

group is selected from


99. The compound or pharmaceutically acceptable salt thereof accordingto claim 84, wherein each R₇ is independently selected from halogen,hydroxyl, C₁-C₃alkyl, and C₁-C₃haloalkyl.
 100. The compound orpharmaceutically acceptable salt thereof according to claim 99, whereineach R₇ is independently selected from halogen, hydroxyl, —CH₃, and—CF₃.
 101. The compound or pharmaceutically acceptable salt thereofaccording to claim 84, wherein n is 0 or
 1. 102. The compound orpharmaceutically acceptable salt thereof according to claim 84, whereineach R₈ is hydrogen or two R₈ groups are taken together to form an oxo.103. The compound or pharmaceutically acceptable salt thereof accordingto claim 84, wherein each R₉ is independently selected from hydrogen,C₁-C₃alkyl, and —C(═O)—C₁-C₃alkyl.
 104. The compound or pharmaceuticallyacceptable salt thereof according to claim 103, wherein each R₉ isindependently selected from hydrogen, —CH₃, —CH₂CH₃, and —CH(CH₃)₂. 105.The compound or pharmaceutically acceptable salt thereof according toclaim 84, wherein the

group is selected from


106. The compound or pharmaceutically acceptable salt thereof accordingto claim 84, wherein L is a linker of 1 to 6 carbon atoms in length,wherein one or more carbon atoms are optionally replaced by C(═O), O,N(R₉), S, C₂-alkenyl, C₂-alkynyl, cycloalkyl, aryl, heterocycle, orheteroaryl, wherein the R₉, C₂-alkenyl, cycloalkyl, aryl, heterocycle,and heteroaryl are each independently substituted with 0, 1, 2, or 3R_(S).
 107. The compound or pharmaceutically acceptable salt thereofaccording to claim 84, wherein one or more carbon atoms of linker L areoptionally replaced by O, N(R₉), cycloalkyl, or heterocycle, wherein theR₉, cycloalkyl, and heterocycle are each independently substituted with0, 1, 2, or 3 R_(S).
 108. The compound or pharmaceutically acceptablesalt thereof according to claim 84, wherein at least two carbon atoms oflinker L are replaced by a heterocycle, each of which is substitutedwith 0, 1, 2, or 3 R_(S).
 109. The compound or pharmaceuticallyacceptable salt thereof according to claim 108, wherein the heterocycleis selected from piperidine and piperazine, each of which is substitutedwith 0, 1, 2, or 3 R_(S).
 110. The compound or pharmaceuticallyacceptable salt thereof according to 107, wherein the heterocycle isselected from


111. The compound or pharmaceutically acceptable salt thereof accordingto claim 84, wherein L is selected from:


112. A compound selected from:N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)oxy)benzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propoxy)propoxy)benzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)benzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propoxy)benzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butoxy)benzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-((5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pentyl)oxy)benzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)nicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)butoxy)benzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)piperidin-1-yl)nicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(ethyl)amino)methyl)piperidin-1-yl)nicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)nicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((((1s,3s)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)nicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;N-((1s,4s)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrazine-2-carboxamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-fluorobenzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperazin-1-yl)benzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)nicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyrimidine-5-carboxamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridazine-3-carboxamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyrazine-2-carboxamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-5-fluoronicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-5-fluoronicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(((2S)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(((2R)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((2S)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((2R)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-methylpiperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((2S)-2-((dimethylamino)methyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((2R)-2-((dimethylamino)methyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)pyridazine-3-carboxamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-(((2-(dimethylamino)ethyl)((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)amino)methyl)piperidin-1-yl)-3-fluorobenzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(((2S)-2-((dimethylamino)methyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-(((2R)-2-((dimethylamino)methyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-5-fluoronicotinamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorobenzamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide;N-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrazine-2-carboxamideN-((1r,4r)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-5-fluoronicotinamide;N-((1r,4S)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-((3S)-3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)pyrimidine-5-carboxamide;N-((1r,4R)-4-((8-cyanoquinolin-5-yl)oxy)cyclohexyl)-2-((3R)-3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)pyrimidine-5-carboxamide;or a pharmaceutically acceptable salt thereof, wherein each hydrogen isindependently and optionally replaced by a deuterium.
 113. Apharmaceutical composition comprising at least one compound orpharmaceutically acceptable salt thereof according to claim 84 or claim112 and a pharmaceutically acceptable carrier.
 114. A method of treatingcancer in a subject in need thereof, comprising administering to thesubject an effective amount of a compound according to claim 84 or claim112, wherein the cancer is selected from prostate cancer, head and neckcancer, skin cancer, sarcoma, renal cell carcinoma, adrenocorticalcarcinoma, bladder cancer, lung cancer, gastric carcinoma, esophagealcarcinoma, pancreatic adenocarcinoma, colorectal cancer, connectivetissue cancer, glioblastoma multiforme, cervical cancer, uterine cancer,ovarian cancer, and breast cancer.
 115. The method according to claim114, wherein the subject has been previously treated with an anti-canceragent chosen from enzalutamide, apalutamide, bicalutamide, darolutamide,flutamide, abiraterone, or a combination thereof.
 116. A method ofinhibiting cell growth, comprising contacting a cell with a compound orpharmaceutically acceptable salt thereof according to claim 84 or claim112.
 117. The compound of Formula (1) according to claim 84, wherein thecompound is a compound of Formula (1A)